DESCRIPTION: (Applicant's Abstract) Basic research and clinical observations support the hypothesis that drugs of abuse achieve their rewarding effects by activating the neuronal circuitry that evolved to mediate incentive-motivating effects of food. Thus, chronic food restriction not only increases the rewarding efficacy of food but also drugs of abuse and direct electrical stimulation of the brain reward system. This laboratory has used lateral hypothalamic electrical stimulation to probe the sensitivity of the brain reward system and investigate mechanisms through which metabolic need, induced by chronic food restriction and diabetes, sensitizes this system. Results of in vivo pharmacological studies attribute reward sensitization to a brain opioid mechanism. In vitro studies have identified several changes in opioid receptor binding, dynorphin peptide levels, and prodynorphin mRNA that could plausibly account for reward sensitization. The research proposed in this application is aimed at further characterization of the brain opioid mechanism that facilitates reward in food-restricted rats. First, two peripheral concomitants of metabolic need-- increased plasma corticosterone and decreased plasma insulin--are investigated as possible physiological antecedents to opioid-mediated reward sensitization. Second, changes in the brain opioid system induced by chronic food restriction are investigated in further detail. Following up on our radioimmunoassay and autoradiographic studies of peptide levels and receptor binding, solution and in situ hybridization will be used to determine whether food restriction produces brain region-specific changes in opioid peptide gene expression. To localize brain regions that are under tonic opioid-mediated inhibitory control during food restriction, c-Fos imrnunohistochemistry will be used to identify neuronal populations activated by opioid antagonists in food-restricted rats. To investigate whether food restriction alters post-receptor events in the opioid signal transduction pathway, [35S]GTP-gammaS autoradiography will be used to identify the neuroanatomical distribution of changes in opioid receptor stimulated G-protein activation. Finally, intracerebral microinjection experiments, guided by outcomes of the preceding studies, will utilize receptor antagonists, antisense oligodeoxynucleotides, and antibodies to opioid peptides to identify brain regions and intrinsic peptide-receptor type combinations that mediate the sensitization of reward.